We present an algorithm for creating high resolution anatomically plausible images consistent with acquired clinical brain MRI scans with large inter-slice spacing. Although large data sets of clinical images contain a wealth of information, time constraints during acquisition result in sparse scans that fail to capture much of the anatomy. These characteristics often render computational analysis impractical as many image analysis algorithms tend to fail when applied to such images. Highly specialized algorithms that explicitly handle sparse slice spacing do not generalize well across problem domains. In contrast, we aim to enable application of existing algorithms that were originally developed for high resolution research scans to significantly undersampled scans. We introduce a generative model that captures fine-scale anatomical structure across subjects in clinical image collections and derive an algorithm for filling in the missing data in scans with large inter-slice spacing. Our experimental results demonstrate that the resulting method outperforms state-of-the-art upsampling super-resolution techniques, and promises to facilitate subsequent analysis not previously possible with scans of this quality. Our implementation is freely available at https://github.com/adalca/papago.
Thalamic atrophy has been associated with exposure to repetitive head impacts (RHI) in professional fighters. The aim of this study is to investigate whether or not age at first exposure (AFE) to RHI is associated with thalamic volume in symptomatic former National Football League (NFL) players at risk for chronic traumatic encephalopathy (CTE). Eighty-six symptomatic former NFL players (mean age = 54.9 ± 7.9 years) were included. T1-weighted data were acquired on a 3T magnetic resonance imager, and thalamic volumes were derived using FreeSurfer. Mood and behavior, psychomotor speed, and visual and verbal memory were assessed. The association between thalamic volume and AFE to playing football and to number of years playing was calculated. Decreased thalamic volume was associated with more years of play (left: p = 0.03; right: p = 0.03). Younger AFE was associated with decreased right thalamic volume (p = 0.014). This association remained significant after adjusting for total years of play. Decreased left thalamic volume was associated with worse visual memory (p = 0.014), whereas increased right thalamic volume was associated with fewer mood and behavior symptoms (p = 0.003). In our sample of symptomatic former NFL players at risk for CTE, total years of play and AFE were associated with decreased thalamic volume. The effect of AFE on right thalamic volume was almost twice as strong as the effect of total years of play. Our findings confirm previous reports of an association between thalamic volume and exposure to RHI. They suggest further that younger AFE may result in smaller thalamic volume later in life.
Background: Digital Imaging and Communications in Medicine (DICOM) is the standard for the representation, storage, and communication of medical images and related information. A DICOM file format and communication protocol for pathology have been defined; however, adoption by vendors and in the field is pending. Here, we implemented the essential aspects of the standard and assessed its capabilities and limitations in a multisite, multivendor healthcare network. Methods: We selected relevant DICOM attributes, developed a program that extracts pixel data and pixel-related metadata, integrated patient and specimen-related metadata, populated and encoded DICOM attributes, and stored DICOM files. We generated the files using image data from four vendor-specific image file formats and clinical metadata from two departments with different laboratory information systems. We validated the generated DICOM files using recognized DICOM validation tools and measured encoding, storage, and access efficiency for three image compression methods. Finally, we evaluated storing, querying, and retrieving data over the web using existing DICOM archive software. Results: Whole slide image data can be encoded together with relevant patient and specimen-related metadata as DICOM objects. These objects can be accessed efficiently from files or through RESTful web services using existing software implementations. Performance measurements show that the choice of image compression method has a major impact on data access efficiency. For lossy compression, JPEG achieves the fastest compression/decompression rates. For lossless compression, JPEG-LS significantly outperforms JPEG 2000 with respect to data encoding and decoding speed. Conclusion: Implementation of DICOM allows efficient access to image data as well as associated metadata. By leveraging a wealth of existing infrastructure solutions, the use of DICOM facilitates enterprise integration and data exchange for digital pathology.
This work presents an anatomically curated white matter atlas to enable consistent white matter tract parcellation across different populations. Leveraging a well-established computational pipeline for fiber clustering, we create a tract-based white matter atlas including information from 100 subjects. A novel anatomical annotation method is proposed that leverages population-based brain anatomical information and expert neuroanatomical knowledge to annotate and categorize the fiber clusters. A total of 256 white matter structures are annotated in the proposed atlas, which provides one of the most comprehensive tract-based white matter atlases covering the entire brain to date. These structures are composed of 58 deep white matter tracts including major long range association and projection tracts, commissural tracts, and tracts related to the brainstem and cerebellar connections, plus 198 short and medium range superficial fiber clusters organized into 16 categories according to the brain lobes they connect. Potential false positive connections are annotated in the atlas to enable their exclusion from analysis or visualization. In addition, the proposed atlas allows for a whole brain white matter parcellation into 800 fiber clusters to enable whole brain connectivity analyses. The atlas and related computational tools are open-source and publicly available. We evaluate the proposed atlas using a testing dataset of 584 diffusion MRI scans from multiple independently acquired populations, across genders, the lifespan (1 day-82 years), and different health conditions (healthy control, neuropsychiatric disorders, and brain tumor patients). Experimental results show successful white matter parcellation across subjects from different populations acquired on multiple scanners, irrespective of age, gender or disease indications. Over 99% of the fiber tracts annotated in the atlas were detected in all subjects on average. One advantage in terms of robustness is that the tract-based pipeline does not require any cortical or subcortical segmentations, which can have limited success in young children and patients with brain tumors or other structural lesions. We believe this is the first demonstration of consistent automated white matter tract parcellation across the full lifespan from birth to advanced age.
Coherence and causality measures are often used to analyze the influence of one region on another during analysis of functional brain networks. The analysis methods usually involve a regression problem, where the signal of interest is decomposed into a mixture of regressor and a residual signal. In this paper, we revisit this basic problem and present solutions that provide the minimal-entropy residuals for different types of regression filters, such as causal, instantaneously causal, and noncausal filters. Using optimal prediction theory, we derive several novel frequency-domain expressions for partial coherence, causality, and conditional causality analysis. In particular, our solution provides a more accurate estimation of the frequency-domain causality compared with the classical Geweke causality measure. Using synthetic examples and in vivo resting-state functional magnetic resonance imaging data from the human connectome project, we show that the proposed solution is more accurate at revealing frequency-domain linear dependence among high-dimensional signals.
PURPOSE: Spaceflight negatively affects sensorimotor behavior; exercise mitigates some of these effects. Head down tilt bed rest (HDBR) induces body unloading and fluid shifts, and is often used to investigate spaceflight effects. Here, we examined whether exercise mitigates effects of 70 days HDBR on the brain and if fitness and brain changes with HDBR are related. METHODS: HDBR subjects were randomized to no-exercise (n = 5) or traditional aerobic and resistance exercise (n = 5). Additionally, a flywheel exercise group was included (n = 8). Exercise protocols for exercise groups were similar in intensity, therefore these groups were pooled in statistical analyses. Pre and post-HDBR MRI (structure and structural/functional connectivity) and physical fitness measures (lower body strength, muscle cross sectional area, VO2 max, body composition) were collected. Voxel-wise permutation analyses were used to test group differences in brain changes, and their associations with fitness changes. RESULTS: Comparisons of exercisers to controls revealed that exercise led to smaller fitness deterioration with HDBR but did not affect brain volume or connectivity. Group comparisons showed that exercise modulated post-HDBR recovery of brain connectivity in somatosensory regions. Posthoc analysis showed that this was related to functional connectivity decrease with HDBR in non-exercisers but not in exercisers. Correlational analyses between fitness and brain changes showed that fitness decreases were associated with functional connectivity and volumetric increases (all r >.74), potentially reflecting compensation. Modest brain changes or even decreases in connectivity and volume were observed in subjects who maintained or showed small fitness gains. These results did not survive Bonferroni correction, but can be considered meaningful because of the large effect sizes. CONCLUSION: Exercise performed during HDBR mitigates declines in fitness and strength. Associations between fitness and brain connectivity and volume changes, although unadjusted for multiple comparisons in this small sample, suggest that supine exercise reduces compensatory HDBR-induced brain changes.
Diffusion tensor imaging (DTI) has been used extensively to investigate white matter (WM) microstructural changes during healthy adult aging. However, WM fibers are known to shrink throughout the lifespan, leading to larger interstitial spaces with age. This could allow more extracellular free water molecules to bias DTI metrics, which are relied upon to provide WM microstructural information. Using a cohort of 212 participants, we demonstrate that WM microstructural changes in aging are potentially less pronounced than previously reported once the free water compartment is eliminated. After free water elimination, DTI parameters show age-related differences that match histological evidence of myelin degradation and debris accumulation. The fraction of free water is further shown to associate better with age than any of the conventional DTI parameters. Our findings suggest that DTI analyses involving free water are likely to yield novel insight into retrospective re-analysis of data and to answer new questions in ongoing DTI studies of brain aging.
PURPOSE: Matching points that are derived from features or landmarks in image data is a key step in some medical imaging applications. Since most robust point matching algorithms claim to be able to deal with outliers, users may place high confidence in the matching result and use it without further examination. However, for tasks such as feature-based registration in image-guided neurosurgery, even a few mismatches, in the form of invalid displacement vectors, could cause serious consequences. As a result, having an effective tool by which operators can manually screen all matches for outliers could substantially benefit the outcome of those applications. METHODS: We introduce a novel variogram-based outlier screening method for vectors. The variogram is a powerful geostatistical tool for characterizing the spatial dependence of stochastic processes. Since the spatial correlation of invalid displacement vectors, which are considered as vector outliers, tends to behave differently than normal displacement vectors, they can be efficiently identified on the variogram. RESULTS: We validate the proposed method on 9 sets of clinically acquired ultrasound data. In the experiment, potential outliers are flagged on the variogram by one operator and further evaluated by 8 experienced medical imaging researchers. The matching quality of those potential outliers is approximately 1.5 lower, on a scale from 1 (bad) to 5 (good), than valid displacement vectors. CONCLUSION: The variogram is a simple yet informative tool. While being used extensively in geostatistical analysis, it has not received enough attention in the medical imaging field. We believe there is a good deal of potential for clinically applying the proposed outlier screening method. By way of this paper, we also expect researchers to find variogram useful in other medical applications that involve motion vectors analyses.
Huntington's disease (HD) is an inherited neurodegenerative disorder that causes progressive breakdown of striatal neurons. Standard white matter integrity measures like fractional anisotropy and mean diffusivity derived from diffusion tensor imaging were analyzed in prodromal-HD subjects; however, they studied either a whole brain or specific subcortical white matter structures with connections to cortical motor areas. In this work, we propose a novel analysis of a longitudinal cohort of 243 prodromal-HD individuals and 88 healthy controls who underwent two or more diffusion MRI scans as part of the PREDICT-HD study. We separately trace specific white matter fiber tracts connecting the striatum (caudate and putamen) with four cortical regions corresponding to the hand, face, trunk, and leg motor areas. A multi-tensor tractography algorithm with an isotropic volume fraction compartment allows estimating diffusion of fast-moving extra-cellular water in regions containing crossing fibers and provides quantification of a microstructural property related to tissue atrophy. The tissue atrophy rate is separately analyzed in eight cortico-striatal pathways as a function of CAG-repeats (genetic load) by statistically regressing out age effect from our cohort. The results demonstrate a statistically significant increase in isotropic volume fraction (atrophy) bilaterally in hand fiber connections to the putamen with increasing CAG-repeats, which connects the genetic abnormality (CAG-repeats) to an imaging-based microstructural marker of tissue integrity in specific white matter pathways in HD. Isotropic volume fraction measures in eight cortico-striatal pathways are also correlated significantly with total motor scores and diagnostic confidence levels, providing evidence of their relevance to HD clinical presentation.
Objectives: To determine whether or not automated FreeSurfer segmentation of brain regions considered important in repetitive head trauma can be analyzed accurately without manual correction. Materials and methods: 3 T MR neuroimaging was performed with automated FreeSurfer segmentation and manual correction of 11 brain regions in former National Football League (NFL) players with neurobehavioral symptoms and in control subjects. Automated segmentation and manually-corrected volumes were compared using an intraclass correlation coefficient (ICC). Linear mixed effects regression models were also used to estimate between-group mean volume comparisons and to correlate former NFL player brain volumes with neurobehavioral factors. Results: Eighty-six former NFL players (55.2 ± 8.0 years) and 22 control subjects (57.0 ± 6.6 years) were evaluated. ICC was highly correlated between automated and manually-corrected corpus callosum volumes (0.911), lateral ventricular volumes (right 0.980, left 0.967), and amygdala-hippocampal complex volumes (right 0.713, left 0.731), but less correlated when amygdalae (right -0.170, left -0.090) and hippocampi (right 0.539, left 0.637) volumes were separately delineated and also less correlated for cingulate gyri volumes (right 0.639, left 0.351). Statistically significant differences between former NFL player and controls were identified in 8 of 11 regions with manual correction but in only 4 of 11 regions without such correction. Within NFL players, manually corrected brain volumes were significantly associated with 3 neurobehavioral factors, but a different set of 3 brain regions and neurobehavioral factor correlations was observed for brain region volumes segmented without manual correction. Conclusions: Automated FreeSurfer segmentation of the corpus callosum, lateral ventricles, and amygdala-hippocampus complex may be appropriate for analysis without manual correction. However, FreeSurfer segmentation of the amygdala, hippocampus, and cingulate gyrus need further manual correction prior to performing group comparisons and correlations with neurobehavioral measures.
PURPOSE: The brain undergoes significant structural change over the course of neurosurgery, including highly nonlinear deformation and resection. It can be informative to recover the spatial mapping between structures identified in preoperative surgical planning and the intraoperative state of the brain. We present a novel feature-based method for achieving robust, fully automatic deformable registration of intraoperative neurosurgical ultrasound images. METHODS: A sparse set of local image feature correspondences is first estimated between ultrasound image pairs, after which rigid, affine and thin-plate spline models are used to estimate dense mappings throughout the image. Correspondences are derived from 3D features, distinctive generic image patterns that are automatically extracted from 3D ultrasound images and characterized in terms of their geometry (i.e., location, scale, and orientation) and a descriptor of local image appearance. Feature correspondences between ultrasound images are achieved based on a nearest-neighbor descriptor matching and probabilistic voting model similar to the Hough transform. RESULTS: Experiments demonstrate our method on intraoperative ultrasound images acquired before and after opening of the dura mater, during resection and after resection in nine clinical cases. A total of 1620 automatically extracted 3D feature correspondences were manually validated by eleven experts and used to guide the registration. Then, using manually labeled corresponding landmarks in the pre- and post-resection ultrasound images, we show that our feature-based registration reduces the mean target registration error from an initial value of 3.3 to 1.5 mm. CONCLUSIONS: This result demonstrates that the 3D features promise to offer a robust and accurate solution for 3D ultrasound registration and to correct for brain shift in image-guided neurosurgery.
PURPOSE: Peritumoral edema impedes the full delineation of fiber tracts due to partial volume effects in image voxels that contain a mixture of cerebral parenchyma and extracellular water. The purpose of this study is to investigate the effect of incorporating a free water (FW) model of edema for white matter tractography in the presence of edema. MATERIALS AND METHODS: We retrospectively evaluated 26 consecutive brain tumor patients with diffusion MRI and T2-weighted images acquired presurgically. Tractography of the arcuate fasciculus (AF) was performed using the two-tensor unscented Kalman filter tractography (UKFt) method, the UKFt method with a reduced fiber tracking stopping fractional anisotropy (FA) threshold (UKFt+rFA), and the UKFt method with the addition of a FW compartment (UKFt+FW). An automated white matter fiber tract identification approach was applied to delineate the AF. Quantitative measurements included tract volume, edema volume, and mean FW fraction. Visual comparisons were performed by three experts to evaluate the quality of the detected AF tracts. RESULTS: The AF volume in edematous brain hemispheres was significantly larger using the UKFt+FW method (p<0.0001) compared to UKFt, but not significantly larger (p = 0.0996) in hemispheres without edema. The AF size increase depended on the volume of edema: a significant correlation was found between AF volume affected by (intersecting) edema and AF volume change with the FW model (Pearson r = 0.806, p<0.0001). The mean FW fraction was significantly larger in tracts intersecting edema (p = 0.0271). Compared to the UKFt+rFA method, there was a significant increase of the volume of the AF tract that intersected the edema using the UKFt+FW method, while the whole AF volumes were similar. Expert judgment results, based on the five patients with the smallest AF volumes, indicated that the expert readers generally preferred the AF tract obtained by using the FW model, according to their anatomical knowledge and considering the potential influence of the final results on the surgical route. CONCLUSION: Our results indicate that incorporating biophysical models of edema can increase the sensitivity of tractography in regions of peritumoral edema, allowing better tract visualization in patients with high grade gliomas and metastases.
Neuronal and glial projections can be envisioned to be tubes of infinitesimal diameter as far as diffusion magnetic resonance (MR) measurements via clinical scanners are concerned. Recent experimental studies indicate that the decay of the orientationally-averaged signal in white-matter may be characterized by the power-law, () ∝ , where is the wavenumber determined by the parameters of the pulsed field gradient measurements. One particular study by McKinnon .  reports a distinctively faster decay in gray-matter. Here, we assess the role of the size and curvature of the neurites and glial arborizations in these experimental findings. To this end, we studied the signal decay for diffusion along general curves at all three temporal regimes of the traditional pulsed field gradient measurements. We show that for curvy projections, employment of longer pulse durations leads to a disappearance of the decay, while such decay is robust when narrow gradient pulses are used. Thus, in clinical acquisitions, the lack of such a decay for a fibrous specimen can be seen as indicative of fibers that are curved. We note that the above discussion is valid for an intermediate range of -values as the true asymptotic behavior of the signal decay is () ∝ for narrow pulses (through Debye-Porod law) or steeper for longer pulses. This study is expected to provide insights for interpreting the diffusion-weighted images of the central nervous system and aid in the design of acquisition strategies.
OBJECTIVE Endoscopic endonasal approaches are increasingly performed for the surgical treatment of multiple skull base pathologies. Preventing postoperative CSF leaks remains a major challenge, particularly in extended approaches. In this study, the authors assessed the potential use of modern multimaterial 3D printing and neuronavigation to help model these extended defects and develop specifically tailored prostheses for reconstructive purposes. METHODS Extended endoscopic endonasal skull base approaches were performed on 3 human cadaveric heads. Preprocedure and intraprocedure CT scans were completed and were used to segment and design extended and tailored skull base models. Multimaterial models with different core/edge interfaces were 3D printed for implantation trials. A novel application of the intraoperative landmark acquisition method was used to transfer the navigation, helping to tailor the extended models. RESULTS Prostheses were created based on preoperative and intraoperative CT scans. The navigation transfer offered sufficiently accurate data to tailor the preprinted extended skull base defect prostheses. Successful implantation of the skull base prostheses was achieved in all specimens. The progressive flexibility gradient of the models' edges offered the best compromise for easy intranasal maneuverability, anchoring, and structural stability. Prostheses printed based on intraprocedure CT scans were accurate in shape but slightly undersized. CONCLUSIONS Preoperative 3D printing of patient-specific skull base models is achievable for extended endoscopic endonasal surgery. The careful spatial modeling and the use of a flexibility gradient in the design helped achieve the most stable reconstruction. Neuronavigation can help tailor preprinted prostheses.
Diffusion tensor imaging studies report childhood adversity (CA) is associated with reduced fractional anisotropy (FA) in multiple white matter tracts in adults. Reduced FA may result from changes in tissue, suggesting myelin/axonal damage, and/or from increased levels of extracellular free-water, suggesting atrophy or neuroinflammation. Free-water imaging can separately identify FA in tissue (FA) and the fractional volume of free-water (FW). We tested whether CA was associated with altered FA, FA, and FW in seven white matter regions of interest (ROI), in which FA changes had been previously linked to CA (corona radiata, corpus callosum, fornix, cingulum bundle: hippocampal projection, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus). Tract-based spatial statistics were performed in 147 psychiatrically healthy adults who had completed a self-report questionnaire on CA primarily stemming from parental maltreatment. ROI were extracted according to the protocol provided by the ENIGMA-DTI working group. Analyses were performed both treating CA as a continuous and a categorical variable. CA was associated with reduced FA in all ROI (although categorical analyses failed to find an association in the fornix). In contrast, CA was only associated with reduced FAin the corona radiata, corpus callosum, and uncinate fasciculus (with the continuous measure of CA finding evidence of a negative relation between CA and FAin the fornix). There was no association between CA on FW in any ROI. These results provide preliminary evidence that childhood adversity is associated with changes to the microstructure of white matter itself in adulthood. However, these results should be treated with caution until they can be replicated by future studies which address the limitations of the present study.
OBJECTIVE: To address the feasibility and predictive value of multimodal image-based virtual reality in detecting and assessing features of neurovascular confliction (NVC), particularly regarding the detection of offending vessels, degree of compression exerted on the nerve root, in patients who underwent microvascular decompression for nonlesional trigeminal neuralgia and hemifacial spasm (HFS). METHODS: This prospective study includes 42 consecutive patients who underwent microvascular decompression for classic primary trigeminal neuralgia or HFS. All patients underwent preoperative 1.5-T magnetic resonance imaging (MRI) with T2-weighted three-dimensional (3D) sampling perfection with application-optimized contrasts by using different flip angle evolutions, 3D time-of-flight magnetic resonance angiography, and 3D T1-weighted gadolinium-enhanced sequences in combination, whereas 2 patients underwent extra experimental preoperative 7.0-T MRI scans with the same imaging protocol. Multimodal MRIs were then coregistered with open-source software 3D Slicer, followed by 3D image reconstruction to generate virtual reality (VR) images for detection of possible NVC in the cerebellopontine angle. Evaluations were performed by 2 reviewers and compared with the intraoperative findings. RESULTS: For detection of NVC, multimodal image-based VR sensitivity was 97.6% (40/41) and specificity was 100% (1/1). Compared with the intraoperative findings, the κ coefficients for predicting the offending vessel and the degree of compression were >0.75 (P < 0.001). The 7.0-T scans have a clearer view of vessels in the cerebellopontine angle, which may have significant impact on detection of small-caliber offending vessels with relatively slow flow speed in cases of HFS. CONCLUSIONS: Multimodal image-based VR using 3D sampling perfection with application-optimized contrasts by using different flip angle evolutions in combination with 3D time-of-flight magnetic resonance angiography sequences proved to be reliable in detecting NVC and in predicting the degree of root compression. The VR image-based simulation correlated well with the real surgical view.
INTRODUCTION: Diffusion tensor imaging detects early tissue alterations in Alzheimer's disease and cerebral small vessel disease (SVD). However, the origin of diffusion alterations in SVD is largely unknown. METHODS: To gain further insight, we applied free water (FW) imaging to patients with genetically defined SVD (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL], n = 57), sporadic SVD (n = 444), and healthy controls (n = 28). We modeled freely diffusing water in the extracellular space (FW) and measures reflecting fiber structure (tissue compartment). We tested associations between these measures and clinical status (processing speed and disability). RESULTS: Diffusion alterations in SVD were mostly driven by increased FW and less by tissue compartment alterations. Among imaging markers, FW showed the strongest association with clinical status (Rup to 34%, P < .0001). Findings were consistent across patients with CADASIL and sporadic SVD. DISCUSSION: Diffusion alterations and clinical status in SVD are largely determined by extracellular fluid increase rather than alterations of white matter fiber organization.
BACKGROUND AND PURPOSE: Free water in the posterior substantia nigra obtained from a bi-tensor diffusion MR imaging model has been shown to significantly increase over 1- and 4-year periods in patients with early-stage idiopathic Parkinson disease compared with healthy controls, which suggests that posterior substantia nigra free water may be an idiopathic Parkinson disease progression biomarker. Due to the known temporal posterior-to-anterior substantia nigra degeneration in idiopathic Parkinson disease, we assessed longitudinal changes in free water in both the posterior and anterior substantia nigra in patients with later-stage idiopathic Parkinson disease and age-matched healthy controls for comparison. MATERIALS AND METHODS: Nineteen subjects with idiopathic Parkinson disease and 19 age-matched healthy control subjects were assessed on the same 3T MR imaging scanner at baseline and after approximately 3 years. RESULTS: Baseline mean idiopathic Parkinson disease duration was 7.1 years. Both anterior and posterior substantia nigra free water showed significant intergroup differences at baseline (< .001 and= .014, respectively, idiopathic Parkinson disease versus healthy controls); however, only anterior substantia nigra free water showed significant longitudinal group × time interaction increases (= .021, idiopathic Parkinson disease versus healthy controls). There were no significant longitudinal group × time interaction differences found for conventional diffusion tensor imaging or free water-corrected DTI assessments in either the anterior or posterior substantia nigra. CONCLUSIONS: Results from this study provide further evidence supporting substantia nigra free water as a promising disease-progression biomarker in idiopathic Parkinson disease that may help to identify disease-modifying therapies if used in future clinical trials. Our novel finding of longitudinal increases in anterior but not posterior substantia nigra free water is potentially a result of the much longer disease duration of our cohort compared with previously studied cohorts and the known posterior-to-anterior substantia nigra degeneration that occurs over time in idiopathic Parkinson disease.
The rate of water exchange across cell membranes is a parameter of biological interest and can be measured by diffusion magnetic resonance imaging (dMRI). In this work, we investigate a stochastic model for the diffusion-and-exchange of water molecules. This model provides a general solution for the temporal evolution of dMRI signal using any type of gradient waveform, thereby generalizing the signal expressions for the Kärger model. Moreover, we also derive a general nth order cumulant expansion of the dMRI signal accounting for water exchange, which has not been explored in earlier studies. Based on this analytical expression, we compute the cumulant expansion for dMRI signals for the special case of single diffusion encoding (SDE) and double diffusion encoding (DDE) sequences. Our results provide a theoretical guideline on optimizing experimental parameters for SDE and DDE sequences, respectively. Moreover, we show that DDE signals are more sensitive to water exchange at short-time scale but provide less attenuation at long-time scale than SDE signals. Our theoretical analysis is also validated using Monte Carlo simulations on synthetic structures.